TGFbeta1 has both tumor suppressor and oncogenic roles in human cancer development, but the mechanisms underlying this change in function remain elusive. Identifying the mechanisms underlying these distinct functions of TGFbeta1 and how this change occurs will provide important new targets for cancer therapy. We have recently developed a TGFbeta1 conditional epidermal expression mouse model to identify tumor stage specific effects and targets of TGFbeta1 expression. Preliminary studies reveal that TGFbeta1 expression in the normal epidermis, benign and malignant skin tumors provokes profoundly distinct responses from the host immune system that are associated with tumor regression or progression. The central hypothesis of this research proposal is that the changing roles of TGFbeta1 during cancer progression are linked to distinct responses of the immune system to tumor cell derived TGFbeta1. Specific Aim 1 tests the hypothesis that the adaptive immune response to epidermally derived TGFbeta1 is stage specific using genetic and immunological means to deplete and restore specific immune cell subsets. The second specific aim is to test the hypothesis that overexpression of TGFbeta1 in the normal epidermis and the resulting inflammation is a tumor-promoting stimulus for epidermal keratinocytes harboring a chemically or genetically activated ras oncogene. Specific Aim 3 tests the hypothesis that NF-kappaB signaling is essential for the stage specific response of the immune system to TGFbeta1 in the normal epidermis and in squamous tumors using in vitro and in vivo biochemical and molecular analysis, and genetic methods to block NF-kappaB signaling. The increased incidence of non-melanoma skin cancer in the general population, and the increasing problem of aggressive SCC of the skin in immunocompromised organ transplant patients represent a significant public health problem. The goal of this research project are to use this conditional expression mouse model to understand how TGFbeta1 produced by developing tumor cells differentially regulates the anti-tumor immune response, so that ultimately therapeutic targets and strategies can be identified that will block the immunosuppressive effects and enhance the anti-tumor inflammatory effects of tumor derived TGFbeta1.